Effect of Rifampicin on Efavirenz Pharmacokinetics in HIV-Infected Children With Tuberculosis

Ren, Yuan; Nuttall, James; Eley, Brian; Meyers, Tammy; Smith, Peter J.; Maartens, Gary; McIlleron, Helen

doi:10.1097/qai.0b013e31819c33a3

Cited by 60 publications

(61 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The large deviation (both positive and negative) from the average in the current and previous studies might explain the modest effect of rifampin in the study populations as a whole. The apparent lack of induction of efavirenz metabolism by rifampin-containing anti-TB therapy in some subjects is contrary to the expected effect of rifampin, but it is consistent with the bimodal effects of rifampin-containing anti-TB therapy on efavirenz plasma concentrations observed in HIV-TB-coinfected patients (13,17,35).…”

Section: Discussionsupporting

confidence: 47%

“…An extensive review of published literature did not find adequate evidence to support a dose increase with rifampin coadministration because of current lack of understanding of the likelihood of under-or overdosing individuals (11). Prior drug-drug interaction studies failed to evaluate genetic contributions to the variability in the induction effect of rifampin (2, 24), were performed in the setting of clinical care, where patients were receiving other antituberculous drugs in addition to rifampin, or did not have an appropriate control period or comparator group (13,20,25,35). To better characterize the effect of rifampin on efavirenz disposition as well as interindividual differences in response to rifampin, we conducted a randomized two-period crossover pharmacokinetic (PK) study in healthy African-American and Caucasian volunteers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Kwara

Tashima

Dumond

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC 0-24 (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC 0-24 ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC 0-24 ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C 24 ) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC 0-24 values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.Efavirenz is an essential component of preferred antiretroviral regimens in treatment of human immunodeficiency virus (HIV) infection in patients coinfected with tuberculosis (TB) (6,32,33). The standard adult dose of 600 mg daily is associated with considerable interindividual variability in plasma concentrations and clinical effects (10,28,38). There is even greater variability in efavirenz concentrations during coadministration with rifampin or rifampin-containing TB therapy (2,13,29). Efavirenz is primarily metabolized by hepatic CYP2B6, with some contributions from CYP3A4/5 (42), CYP2A6 (30), and UGT2B7 enzymes (1). Rifampin was shown to be a potent inducer of CYP2B6 activity when bupropion was used as a probe of enzyme activity (22). Among healthy volunteers, rifampin caused 26% and 20% reductions in mean efavirenz area under the curve (AUC) and maximum concentration (C max ), respectively (2). Among HIV-TB-coinfected patients, mean reductions of 24% and 25% in efavirenz AUC and C max , respectively, were reported with rifampin coadministration. In the above-mentioned studies, some subjects had higher efavirenz plasma exposure with rifampin (compared with that when off rifampin), suggesting a lack of a signif...

show abstract

Section: Discussionsupporting

confidence: 47%

mentioning

confidence: 99%

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Kwara

Tashima

Dumond

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Rifampin is a bacterial RNA polymerase inhibitor that is used to treat tuberculosis and nontuberculosis mycobacterial infections and is a potent CYP and P-glycoprotein inducer (17,31). Rifampin is metabolized by B-esterases to 25-desacetyl-rifampin (16) and is an autoinducer of metabolism.…”

mentioning

confidence: 99%

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

Vourvahis

Davis

Wang

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile exhibiting potent antiviral activity against wild-type HIV and several clinically relevant NNRTI-resistant strains. Lersivirine, a weak inducer of the cytochrome P450 (CYP) enzyme CYP3A4, is metabolized by CYP3A4 and UDP glucuronosyltransferase 2B7 (UGT2B7). Two open, randomized, two-way (study 1; study A5271008) or three-way (study 2; study A5271043) crossover phase I studies were carried out under steady-state conditions in healthy subjects. Study 1 (n ‫؍‬ 17) investigated the effect of oral rifampin on the pharmacokinetics (

show abstract

“…Children are one-third as likely to receive ART as adults, 1 and treatment selections are limited by a lack of pediatric formulations, the instability of some liquid formulations at room temperature, and drug interactions during treatment for tuberculosis and bacilli Calmette-Guérin (BCG) coinfections. [2][3][4][5] HIV-infected infants in resource-limited settings are also more likely to have been exposed to short-course or single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT). This exposure may lead to poor virologic outcomes in infants initiating ART with NVP-based regimens, the most common first-line ART regimen in resource-limited settings, as a result of persistent nevirapine-associated resistance mutations.…”

mentioning

confidence: 99%

Rapid Development of Antiretroviral Drug Resistance Mutations in HIV-Infected Children Less Than Two Years of Age Initiating Protease Inhibitor-Based Therapy in South Africa

Taylor

Hunt²,

Abrams

et al. 2011

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Data on the development of antiretroviral drug resistance in HIV-1-infected children receiving protease inhibitor (PI)-based antiretroviral therapy (ART) are limited. We examined antiretroviral resistance among a cohort of 323 South African HIV-infected children < 2 years old exposed to nevirapine for prevention of mother-to-child transmission. Ritonavir (RTV) was used initially for 138 children who were < 6 months old or receiving antimycobacterial therapy; otherwise children received lopinavir/ritonavir (LPV/r)-based ART. HIV-1 population sequencing of the pol gene was conducted on all pretreatment samples and on posttreatment samples for children who did not achieve HIV-1 plasma RNA < 400 copies/ml by 52 weeks. Among children in the cohort, 38 died, 22 had < 24 weeks follow-up, 209 achieved virologic suppression, and 54 did not. Of 41 children without virologic suppression with posttreatment HIV genotype data available, major resistance mutations were found in 32 (78%): 14 (36%) had PI mutations including V82A, M46I, and L90M; 29 (71%) had M184V/I; and three had NNRTI mutations (K103N, Y181C, and G190A). Among the children who did not achieve virologic suppression, none of the seven children treated exclusively with LPV/r developed PI-related mutations, compared with 14 of 32 (44%) who received RTV-based regimens ( p = 0.036); PI genotypes were unavailable for two children. Seventy-eight percent of children without virologic suppression developed resistance mutations that impact second-line ART options. Only children who received RTV-based ART developed major PI-related resistance mutations, and use of this regimen should be avoided.

show abstract

Effect of Rifampicin on Efavirenz Pharmacokinetics in HIV-Infected Children With Tuberculosis

Abstract: Concomitant rifampicin-based antitubercular treatment was not an important determinant of efavirenz concentrations. The substantial proportion of participants with estimated Cmin <1 mg/L could result in the rapid emergence of efavirenz-resistant mutations and treatment failure.

Cited by 60 publications

References 12 publications

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

Rapid Development of Antiretroviral Drug Resistance Mutations in HIV-Infected Children Less Than Two Years of Age Initiating Protease Inhibitor-Based Therapy in South Africa

Contact Info

Product

Resources

About